Multiple myeloma (MM) affected 14,400 new individuals in the United States in 2001, with 50,000 total patients, and remains incurable despite conventional and high dose therapies. In order to overcome resistance to current therapies and improve patient outcome, novel biologically-based treatment approaches are needed which target mechanisms whereby MM cells grow and survive in the BM. Our preliminary in vitro studies show that the proteasome inhibitor PS-341 mediates apoptosis of resistant MM cells, inhibits binding of MM cells to bone marrow (BM) stromal cells, and inhibits growth and survival cytokines in the BM milieu. This agent also decreases tumor cell growth and prolongs survival in a murine model, and phase II clinical trials demonstrate remarkable clinical activity, even complete responses, in patients with refractory relapsed disease. In this context, we propose to define the molecular mechanism whereby this and other agents mediate anti-MM activity, as well as mechanisms conferring resistance to these novel agents. To achieve this goal, we will define the role of the ubiquitin-proteasome pathway in MM pathogenesis and therapy (Specific Aim 1); define the molecular sequelae of proteasome inhibitor treatment in MM cells in vitro (Specific Aim 2); evaluate XBP-1 as a target of proteasome inhibitor therapy (Specific Aim 3); and evaluate response and resistance mechanisms to proteasome inhibitors in vivo using animal models and in derived clinical trials (Specific Aim 4). These studies will not only delineate the underlying mechanisms mediating anti-MM activity of currently available proteasome inhibitors, but also provide the framework for development of more potent and less toxic targeted therapies.